PROJECT SUMMARY Colorectal cancer (CRC) is the third most common and second most lethal cancer in the United States. Since the early 1990s, colorectal cancer (CRC) incidence in younger U.S. adults (<50 years) has increased 1.5% per year in men and 1.6% per year in women and currently comprises 11% of colon cancers and 18% of rectal cancers. Furthermore, colorectal cancers diagnosed in people <50 years of age tend to be more advanced than if diagnosed at an older age, increasing the urgency to address this emerging public health problem. There are currently no prevention programs broadly offered for this age group; we plan research to address this gap. The overall goal of the study is to identify CRC susceptibility factors specific to this age group and to provide the first comprehensive evidence-based guideline for CRC screening for people <50 years of age. Our primary hypothesis is that obesity, physical inactivity and diabetes may have major effects on CRC in younger people, exacerbated by recent temporal changes in the prevalence of these factors. Our specific aims are: 1) to comprehensively characterize risks for CRC in young people (<50 years of age), with respect to family history of CRC, lifestyle and environmental factors and genetics and 2) to develop predictive models from this information to determine who could potentially benefit from screening at a younger age. We will test our hypotheses in data from three large research consortia: the Colon Cancer Family Registry (CCFR), the Colorectal Cancer Transdisciplinary (CORECT) Study and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Our study includes comprehensive clinical, epidemiologic and genetic data on >2,000 CRC cases and controls <50 years of age and on >14,000 CRC cases and controls ?50 years of age. This is the first study to comprehensively assess environmental (including lifestyle) and genetic risks in those <50 years of age and is the first to develop a risk prediction tool specifically for this age group. This project is important because it has the potential for significant impact on clinical practice, as knowledge gained from the investigation could lead to changes in approach to primary and secondary prevention of CRC in people <50 years of age.